1-48663232-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032785.4(AGBL4):c.644G>A(p.Arg215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,756 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (116 hom.)
• Consequence: AGBL4 NM_032785.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.902

Genes affected

AGBL4 (HGNC:25892): (AGBL carboxypeptidase 4) Predicted to enable metallocarboxypeptidase activity and tubulin binding activity. Predicted to be involved in C-terminal protein deglutamylation; defense response to virus; and protein side chain deglutamylation. Predicted to act upstream of or within several processes, including axonal transport of mitochondrion; positive regulation of ubiquitin-dependent protein catabolic process; and regulation of blastocyst development. Located in Golgi apparatus; centriole; and ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014713407).
• BP6: Variant 1-48663232-C-T is Benign according to our data. Variant chr1-48663232-C-T is described in ClinVar as [Benign]. Clinvar id is 3055894.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL4	NM_032785.4	c.644G>A	p.Arg215Gln	missense_variant	7/14	ENST00000371839.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL4	ENST00000371839.6	c.644G>A	p.Arg215Gln	missense_variant	7/14	2	NM_032785.4	P1
AGBL4	ENST00000416121.5	c.182G>A	p.Arg61Gln	missense_variant	3/7	1
AGBL4	ENST00000371838.5	c.644G>A	p.Arg215Gln	missense_variant	7/9	5

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3326 AN: 152004 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00549 AC: 1367 AN: 249200 Hom.: 39 AF XY: 0.00419 AC XY: 567 AN XY: 135178

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00235 AC: 3441 AN: 1461636 Hom.: 116 Cov.: 30 AF XY: 0.00207 AC XY: 1502 AN XY: 727090

Gnomad4 AFR exome AF: 0.0774

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.00532

GnomAD4 genome AF: 0.0219 AC: 3336 AN: 152120 Hom.: 110 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74372

Gnomad4 AFR AF: 0.0744

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00406 Hom.: 37

Bravo AF: 0.0242

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0666 AC: 262

ESP6500EA AF: 0.000482 AC: 4

ExAC AF: 0.00654 AC: 790

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AGBL4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	19
Dann	Benign	0.86
DEOGEN2	Benign	0.0027	T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.10	N;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.82	N;.;N
REVEL	Benign	0.0070
Sift	Benign	0.64	T;.;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.19
MVP		0.030
MPC		0.15
ClinPred		0.010	T
GERP RS		2.6
Varity_R		0.039
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75333004; hg19: chr1-49128904; COSMIC: COSV61890996;